PT98424A - PROCESS FOR THE PREPARATION OF NEW SUBSTITUTED PIPERIDINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

The present invention relates to a group of compounds which are novel substituted piperidines and which act to inhibit the synthesis of cholesterol in mammals and in fungi.

Description

PROCESS FOR PREPARING NEW REPLACED PIPERIDINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Field of the Invention The present invention relates to a group of compounds which are novel substituted piperidines and which act as inhibitors of cholesterol synthesis in mammals and fungi.

Background of the invention

Vascular diseases, due to their effects on the brain, heart, kidney and extremities, and other vital organs, are one of the leading causes of morbidity and mortality in the United States and most western countries. In this regard, much research has been done on atherosclerosis, atherosclerosis and lipidemias, with particular reference to cholesterol. In particular, there is convincing evidence of an inverse relationship between elevated serum cholesterol and the incidence of atherosclerosis and its sequelae. There has been great interest in reducing serum cholesterol in recent years. However, some studies have shown that, even with radical reductions in dietary cholesterol, only a modest decrease of cholesterolemy is achieved by 10 to 15%. Thus, it is considered that the higher reductions in cholesterol -2-

require other therapeutic measures including the physiological inhibition of cholesterol synthesis in the body. Enzymatic cholesterol biosynthesis is a complex process that requires a set of 25 reaction steps. The scheme can be divided into three stages: (1) the conversion of acetic acid to meralonic acid; (2) converting the meralonic acid to squalene; and (3) the conversion of squalene to cholesterol. In this last phase of cholesterol biosynthesis, squalene is converted to squalene-2,3-epoxide by oxidation a reaction catalyzed by squalene monooxygenase, also known as squalene epoxidase. The squalene 2,3-epoxide is then cyclized to form lanosterol, the first sterol to be formed. The cyclization of 2,3-oxalo-squalene in lanosterol is a fundamental reaction in the biosynthesis of cholesterol in mammals. The reaction is catalyzed by the microsomal enzyme 2,3-oxide-squalene-lanosterol-cyclase. (see, for example, Taylor, Frederick R., Kandutsch, Andrew A., Gayen, Apurba K., Nelson, James A., Nelson, Sharon S., Phirwa, Seloka and Spencer, Thomas A., " , 25-Epoxysterol Metabolism in Cultured Mammalian Cellsand Repression of 3-Hydroxy-3-methylagglutaryl-CoA Reductase ", The Journal of Biological Chemistry, 261 (1986) 15039-15044, incorporated herein by reference).

In addition, it has recently been reported that certain compounds, such as aryl alamines, act as potent inhibitors of 3-

of fungal squalene epoxidase. Fungal infections (mycoses) are widespread throughout the world. Only a few structural classes of compounds currently meet the requirements of modern chemotherapy for its treatment, and the investigation of novel types of active substances is of fundamental therapeutic importance. (See, in general, Stutz, Anton, " Allylamine Derivatives-A New Class of Active Substances in Antifungal Chemothe-rapy ", Angew. Chem. Int. Ed. Engl., 26 (1987) 320-328.

As squalene epoxidase inhibitors in animals, the compounds of the present invention are accepted as useful in the treatment of fungal infections due to inhibition of cholesterol synthesis.

Summary of the Invention The present invention relates to compounds of general formula

 € ƒâ € ƒâ € ƒR (A) Y is -A- (Alk)

-E- (Alk +) - CH- in which A-4-

represents a -CH 2 -, -CH- or CH- or

NR a group of the formula - in which R represents a

hydrogen atom or a C 1-4 lower alkyl group; D and E each independently represent a direct bond, a -CH 2 - group or a group of the formula --R ' 0 Jj-R '" -CH 2 -N-, -N-, -CN-, -CN-, -N-C, or -N-C-group wherein R " and R1 " are each independently a hydrogen atom or a lower alkyl group having the proviso that N is not -CH2-N- or N-when D represents one of such groups and E is not a group of the formula R " R '" -N R " R "RI, N-RI "

Or -N-C- when D represents one of such groups; and D and / or E do not represent a group R " R " -N R1 " R " 0 R " N -R " 1

(C1 -C3) -alkyl of the general formula -CN-, -CN-, -N-C- or -N-C- when A represents a group -CH (CF3); (A1q2), (A1q2) and (Alk2) each independently represent a straight-chain alkylene group having zero to 5 carbon atoms and optionally containing 1 to 3 methyl groups as (S) substituent; with the proviso that (Alk2) does not have zero carbon atoms; or (AIq1) > (AIq2) and (AIq3) are each independently -5-

a straight chain alkenylene group having 2 to 6 carbon atoms and 1 to 2 double bonds and optionally containing 1 to 3 methyl group (s) as the substituent (s), represents a group which is in the 3 or 4 position of the piperidine ring of general formula

in which R 3 represents a C 1-4 alkyl group, R 4 and R 5 each independently represent a hydrogen atom or a C 1-4 lower alkyl group and n is 1 or 3; and R 2 represents a hydrogen atom or a hydroxy or lower alkyl group C? 1-3

A preferred aspect of the present invention are the compounds wherein R1 is a group of the formula:

as used herein: (a) the term alkylene refers to methylene, ethylene, propylene, butylene, pentylene and hexylene groups; (b) the term alkenylene refers to any of the foregoing alkylene groups containing 1 or 2 double bonds in its chain; and (c) the designation of C1-6 lower alkyl refers to methyl, ethyl, propyl, and isopropyl groups; (d) the term lower alkyl, refers to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl groups.

Also, as used in this application, the R2 substituent may be in any of the 2 to 6 positions of the piperidine nucleus, except in the position occupied by the group R 2. In the piperidine nucleus there may exist up to three such substituents when the substituent is not the hydrogen atom.

Detailed description of the present invention

In general, the compounds of the present invention are prepared by the following methods. The synthesis of all the synthetic products of this invention begins with the synthesis of the intermediate compound 7-

gave A; as described in detail below.

Preparation of 3- and 4-substituted piperidine intermediates Intermediate A, shown below in Reaction Scheme A, wherein R4 and R4 are as defined above, may be prepared as described.

Reaction Scheme A (ch3ch2o) 2 CH (CH2) nC02CH2CH3

η-Bu-Li, THF - wittig reaction 2

1) 10% Pd / C, H2 - ► 2) LAH / THF

R 2 ·

H co2-ch2ch3

Reduction 3

Intermediate A-8-

First, a Wittig reaction is carried out wherein the alkyl phosphonate of formula wherein n is zero or an integer from 1 to 3 and R 1 represents a lower alkyl group is reacted with a 3- or 4-piperidinone 2 for piperidine intermediate substituted 2 compounds of compounds 1 and 2 or are commercially available or are readily prepared by conventional techniques. The piperidine of formula 2 contains a protecting group (PG) at the position of the nitrogen atom. Suitable protecting groups are known and include benzyl, benzyloxy, p-methoxybenzyl groups, as well as other protecting groups, which are not to be considered as limiting. The alkylphosphonate of general formula is chosen in such a way that R 2 and n represent the desired groups for the final product. It is to be understood that although the alkyl 1-phosphonate represented by the general formula I is a triethyl ester, other alkyl esters such as methyl, propyl or isopropyl ester may also be used, for example, which is not to be considered as limiting.

The alkyl 1-phosphonate of formula I is dissolved in an anhydrous aprotic solvent, such as tetrahydrofuran, to which is added a solution of n-butyllithium in hexane, or another similar basic agent, in an amount approximately equimolar at a low temperature (-78 ° C). Add the appropriate piperidinone of formula 2 in tetrahydrofuran to dropwise,

reaction mixture in an approximately equimolar ratio with the alkyl 1-phosphonate of Formula 1. The piperidinone 2 is chosen so that the location of the carbonyl oxygen is the same as the desired substitution end product, i.e., the 3- or 4- position. The reaction material is warmed to room temperature and the reaction is preferably carried out under inert atmosphere, such as the argon atmosphere. The intermediate of formula 3 may be separated from the solution and purified by standard techniques. For example, the reaction mixture may be diluted with saturated ammonium chloride solution, washed with 10% sodium hydroxide solution, dried over magnesium sulfate and evaporated to give an oil not purified. The crude oil can be purified by conventional techniques, such as chromatography. The purified piperidine substituted compound of formula 3 is then reduced to the intermediate A wherein it has the meaning defined above, in two steps, as follows. This reduction achieves three results. The carbon double bond of the piperidine is hydrogenated; the terminal ester group is reduced to a -CH20H group; and the protecting group is separated from the nitrogen atom of the piperidine nucleus. The intermediate compound of formula 3 is first converted to the corresponding acid addition salt by treatment with a saturated solution of hydrochloric acid in methanol, for example, followed by renewal of the solvent. The reduction is carried out by known techniques. -10-

For example, the residue is dissolved in anhydrous ethanol and transferred to a Parr hydrogenation vessel. A catalytic amount of 10% palladium on charcoal (Pd / C) is added to the vessel loaded with hydrogen under pressure of 3.5 kg / cm (50 psi). After stirring for several hours, the catalyst is filtered through Celite, for example, and the solvent is removed in vacuo. After removal of the solvent, the residue is neutralized with 10% sodium hydroxide solution. The resulting product is extracted by known techniques.

For example, the aqueous phase is extracted with diethyl ether and the extracts are dried over magnesium sulfate. Removal of the solvent in vacuo gives an oil, which is then dissolved in anhydrous tetrahydrofuran and treated with an excess of lithium aluminum hydride (LAH). The reaction is stopped by conventional techniques, such as those described in Fieser & Fieser, vol. 1, p. 584 and the solvent is removed to give an oil which is purified by known techniques. For example, the oil may be purified by chromatography on silica gel using 25% hexane ethyl acetate solution followed by a 20% methanol / chloroform solution as eluent. The concentration of the methanol / chloroform fractions gives the desired product, the intermediate compound of formula A.

Reaction Scheme I

The compounds represented by the general formula I may be prepared according to the following reaction scheme: R,

Br -A- (Alk1) -C-O-Et

N-alkylation

Intermediate A

-A- (Alk1) -C-O-Et R " - N - (A1q2) -CH3

Amidation

Intermediate Ir2 \ ... 8 r

Formula A A general formula I is a representation of the general formula A in which D represents a group -CN-, A represents a CH 2, 3-methylene or -CH (A1q3) represents an alkylene radical having zero carbon atoms, (Alk1), (Alk2) and R8 'have the meanings given in general formula A and E represents a direct bond.

The first step of the reaction is N-alkylation of the piperidine intermediate of formula A by a bromoalkyl ester represented by the general formula. It is to be understood that the abbreviation Br in this example throughout this specification represents a bromine atom ; however, a chloroalkyl ester may also be used. The intermediate behaves as radical substituents represented by the symbols and R 2, as defined above. Other esters other than the ethyl esters (ET), such as methyl, n-propyl or isopropyl ester, may be used.

Suitable starting compounds are the bromoalkyl ester of formula 1 wherein A and (A1) are the desired groups for the final product and intermediate compound A in which R1 and R2 have the meanings intended for the final product represented by the general formula I. The compound is commercially available or readily prepared by conventional techniques. The alkylation reaction can be carried out by well-known techniques. The bromoalkyl ester and the intermediate compound A are usually mixed in a molar ratio of about 1: 2 in a solvent such as benzene and the reaction mixture is heated under reflux under an inert atmosphere for approximately 16 hours. Alternatively, the bromoalkyl ester J 1, the intermediate formula A and triethylamine may be mixed in equimolar amounts. The intermediate compound of formula I is then collected from the reaction mixture and purified by known techniques. For example, the reaction mixture is concentrated under reduced pressure and then taken up in diethyl ether and filtered to give an intermediate compound I as depicted which can be purified by flash chromatography. The next step of the reaction scheme is an amidation reaction between the intermediate of Formula I and a substituted amine of Formula 2. Compounds 2 are either commercially available or are readily prepared by standard procedures. The substituted amine 2 is chosen so that R " and (A1q2) have the same definitions as RH and Al2O in the final product represented by formula I. The substituted amino 2 is contacted with the intermediate compound I in a molar ratio of 1: 1 to 2: 1 in the presence of 2-hydroxypihidine and heat at a temperature of about 60 ° C for several hours. The solution is poured into water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The final product is purified using well known chromatographic techniques such as flash chromatography

Reaction Scheme II

The amides of formula I, prepared as defined above, may be reduced to the corresponding amine of formula II according to the following reaction scheme:

LAH

FORMULA I

FORMULA II The general formula II is a representation of the general formula A in which D represents a group of general formula

R " (A1q2) represents an alkylene radical having zero carbon atoms and (Alk2), (Alk2), (Alk2) 2, , R2 and R " are as defined in general formula I.

Dissolve the amide prepared by the method depicted in Reaction Scheme I in tetrahydrofuran. The solution is cooled to about 10 ° C and a reducing agent is added,

such as lithium aluminum hydride. The reaction mixture is stirred overnight at ambient temperature, for example, followed by heating the reaction mixture under reflux.

The solution is then cooled to ambient temperature, diluted by standard techniques such as those described by Fieser & Fieser, supra, and the solvent is removed. The resulting oil can be purified by standard techniques. The resulting oil can be dissolved in diethyl ether, filtered and treated with anhydrous hydrochloric acid. The resulting precipitate is filtered and recrystallised from ethyl acetate / isopropyl alcohol, for example, to give a final product of general formula II.

Reaction Scheme III

Alternatively, the amide of formula I, as described above, can be converted to the corresponding amide of formula III.

Formula III is a representation of formula A in which D represents a group of formula

R, and-N R " (A1q3) represents an alkylene group having zero carbon atoms, E represents a direct bond and (Alk2, (Al2), R1, R 2 and R "have the meanings given above for the general formula A.

The amide of formula I is reacted with triethyloxonium tetrafluoroborate (Et3 OBF3) followed by the addition of an amine of formula R " -NHg. The amine is chosen so that R 1 " represents the same group as is intended to exist in the final product.

An amide prepared according to Reaction Scheme I is dissolved in methylene chloride and treated with an approximately equimolar amount of tri-ethyloxonium tetrafluoroborate and then with an excess of the desired substituted amine

The reaction mixture is stirred overnight at room temperature, followed by heating under reflux.

Then, the reaction mixture is cooled to room temperature, diluted with aqueous sodium hydroxide, extracted with an organic solvent, dried over a drying agent such as, for example, magnesium sulfate , and concentrated under reduced pressure. The resulting oil can be purified,

by usual techniques. The resulting oil can be dissolved in diethyl ether, filtered and treated with anhydrous hydrochloric acid. A precipitate results which is filtered and recrystallized from ethyl acetate / isopropyl alcohol, for example to give an end product of general formula III.

Reaction Scheme IV

Amidines of general formula IV can be prepared by the following reaction scheme. The general formula IV is a representation of formula A in which D represents a group of formula

R " NH 1 !! A represents a -CH 2 or -CH 2 -alkyl group represented by an alkyl group having zero carbon atoms, E represents a direct bond and (Alk%), (Alk%), R1, Q R " have the meanings given above for the general formula A.

N = C - (Alk 2) - CH 3 1 +

MeOH 2 ethyl Pinner reaction * NH HCl

(A1q2) -CH3 +

N-A-CH2), -NH2 Intermediate II

Amidine Formation Reaction 3

R 2 R "

N-A - (A1 q1) -N

N H

II c - (AI q2) - CH3

R 1

Formula IV The first step of the reaction sequence is the reaction of the Pinner reaction which converts the alkylnitrile of formula (II) in which (A1q2) has the same definition as intended for the final product into the imidate ester 3. Compound or is commercially available or can be readily prepared by standard techniques. The alkyl lithium and an appropriate alcohol, such as methanol, are mixed in approximately equimolar amounts in a solvent, such as diethyl ether, and cooled to 0 ° C, then saturated and washed with hydrochloric acid and stirred overnight at 0 ° C to room temperature. The imidate ester 3 is concentrated under reduced pressure, and can be purified by -19- γ. known techniques, such as trituration with diethyl ether, filtration and air drying. The resulting salt is then mixed with an equimolar amount of the appropriate N-substituted alkylamine-piperidine represented by the intermediary of formula II in a reaction with amidine formation.

Intermediate of formula II can be prepared as follows:

Reaction Scheme IV A

+ R

Br-A- (Alk1) C = N

. I 1

Intermediate A

Nal / toluene-N-Alkyl

R 1 is N-A- (Alk +) C R

LAH 2 'r 2,

Intermediate of formula A is chosen so that R 1 and R 2 have the meanings intended for the final product and the bromoalkylcyano compound of formula (J) is chosen such that wherein A and (Alk) have the same meanings -20-

than the intended final product. The compound of formula 1 is either commercially available or can be readily prepared by well-known techniques. The reactants are combined in an inert solvent, such as toluene, with a catalytic amount of sodium iodide and heated under reflux. The alkylcyano-piperidine of formula 2 is isolated by partitioning between diethyl ether and sodium hydrogen carbonate.

The alkylcyano-piperidine 2 is then mixed dropwise with an approximately equimolar amount of powdered lithium aluminum hydride dissolved in tetrahydrofuran. The reaction mixture is stirred at room temperature, diluted with water and sodium hydroxide, filtered, washed, dried over magnesium sulfate and concentrated under reduced pressure to give intermediate of formula II.

The intermediate compound II and the imidate ester hydrochloride of Formula 2 are then mixed in approximately equimolar amounts and allowed to stand overnight at room temperature. The final product of general formula IV may be purified by conventional techniques, such as recrystallization from ethyl acetate / isopropyl alcohol, for example to give the final product of formula IV. -21- **

The above-mentioned amidine of formula IV, prepared by the process described above, can be hydrolyzed by treatment with aqueous sodium hydroxide to form a amine of general formula V.

NaOH

R " NH

A- (Alk1) -N -C (Alk2) -CH3 Formula IV

R 2

R

R " O, N-A- (Alk1) -N-C- (Alk2) -CH3 Formula V The formula V is a representation of formula

wherein A represents a group of the formula -N-C-, A is a -CH2 " or -CH 2 - (Alk) 2 represents an alkylene radical having zero carbon atoms, E represents a direct bond and (Alk 1), (Alk 2), R 2, R 2 and R 4; have the meanings given above for general formula A. The final product of formula V, in the form of its hydrochloride, can be collected by filtration and air-dried. -22-

The amide of formula V, prepared by the process described above, can be treated with a blowing agent, such as triethyloxonium tetrafluoroborate, followed by the introduction of an excess amount of a substituted amine of the formula H2 NR " ' to form a substituted amidine of general formula VI.

R 2 N-A- (Alk +) -N-C- (Alk 2) -CH 3

R 1 (1) Et 30 BF 2 (2)

Formula V

R 2

R 1

R " N-A- (Alk1) -A-C (Alk2) -CH3 Formula VI

The general formula VI corresponds to the general formula A in which D represents a group of the general formula -NH- A is -CH2 - or -CH-, A1q2 represents a radical alkylene having zero carbon atoms, E represents a direct bond and (A1q2), (A1q2), R2, R2 and R3; have the meanings given above for the general formula A. The amine of formula H2 NR is chosen. Tf. in such a way that R, f > has the meaning given for the final product. The final product of formula VI can be purified according to well-known techniques. The resulting oil can be dissolved in diethyl ether, filtered and treated with anhydrous hydrochloric acid. A precipitate results which, filtered and recrystallized from ethyl acetate / isopropyl alcohol, for example, gives the final product VI.

In addition to those mentioned above, complexed compounds whose alkyl side chain may contain an amine group and an amide group or an amine group and an amide group or an amide group and an amidine group can be prepared by the following reaction schemes.

Reaction Scheme VII

Compounds of formula VII may be prepared according to Reaction Scheme VII. The general formula VII represents a general formula I in which A represents a group OOH and R?

-CHO- or -CH-, D is -CN-, and R 1 is -N- and (Alk 1) · (Alk 2), (Alk 3 R 1, R 2 and R 2 have the same meanings as defined above for the general formula A:

N-A- (Alk J-C-O-Et

Intermediate 1

R11 R + HN- (Alk2) -N- (Alk3) -CH3

Amidation *

0 R " (Alk1) -CN- (Alk2) -N- (Alk3) -CH

The intermediate compound I is prepared as described in detail above in Reaction Scheme I. The intermediate compound I is then reacted with the diamine in a molar ratio of about 1: 1 to 1: 2 in the presence of 2-hydroxypyridine. The diamine is commercially available or is readily prepared by the usual techniques. The diamine | is taken so that the groups represented by r ', R ", (Alq2) and (Alk3) have the desired definitions for the final product represented by the general formula VII. The reactants are then heated to a temperature of about 60 ° C.

The resulting compounds of general formula VII can be extracted and purified by conventional methods. The resulting oil can be dissolved in diethyl ether, filtered and treated with anhydrous hydrochloric acid. The resulting precipitate is filtered and recrystallized from ethyl acetate / isopropyl alcohol, for example, to give the final product of formula VII. /

The subsequent treatment of the compounds of formula VII, prepared by the method described above, with an alkylating agent, such as triethyl oxo tetrafluoroborate, followed by introduction of an amount of excess amine. in the substituting the general formula H2NR, U gives the compounds of formula VIII.

R (1) Et30BF4 (2) Rw NH

v 0 R " R 2 pNN-A- (Alk1) -C1-6- (Alk2) -N- (Alk3) -CH3

R

Formula VII

Rw -N R " R N-A- (Aiqi) -C '- (Alk2) -yl- (Alk3) -CH3

Formula VIII The general formula VIII corresponds to the general formula " H 3

R '" -N R " HIA in which A represents a -CH 2 - or -CH- group, D represents a group -CN-, E is -N (e), (Alk), (Alg g), ( Alk 3), R 1, R ', R 1 and R 2 have the meaning

as defined above for the general formula A.

The amine of the formula H 2 NR 1 is chosen. such that R 1 '' is the same groups as R 1 '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' An amide, prepared according to Reaction Scheme VII, is dissolved in methylene chloride and treated with an approximately equimolar amount of triethyloxonium tetrafluoroborate followed by an excess amount of the appropriate substituted amine. The final product of general formula VIII can be purified by the usual techniques. The reaction mixture is stirred overnight at room temperature, followed by heating under reflux. The solution is then cooled to room temperature, diluted with aqueous sodium hydroxide, extracted with an organic solvent, dried over a drying agent such as magnesium sulfate, under reduced pressure. The resulting oil can be purified by conventional techniques and then dissolved in diethyl ether, filtered and treated with anhydrous hydrochloric acid. A precipitate results which is collected by filtration and recrystallized from ethyl acetate / isopropyl alcohol, for example, to give the final product of formula VII. -27-

Reaction Scheme IX

Compounds of formula IX may be prepared by the following method. The general formula IX is a particular aspect of the general formula A in which A represents a -CH 2 - or CH-

D represents a group of the formula -N-, E is 0 R " a group of the formula -CN- and (A1q2) (Alk3) (R3), R4 and R4 are as previously defined for formula A.

R N-A- (Alk1) -NH

Br- (Alk-C-O-Et N-Alkylation

1 Intermediate II

R " -A- (Alk1) -N- (Alk2) -C-O-Et + H-N- (Alk3) -CH3

Intermediate III

Amidation R 0 R "

The first step of Reaction Scheme IX is the N-α-alkylation of the N-substituted piperidine represented by the intermediary -28- -28-N (Alk) -N- (Alk1) -N- (Alk2) -CN- (Alk3) -

S of general formula II (of Reaction Scheme IVA), the methyl ester of formula II. Suitable starting compounds are a bromoalkyl ester of formula (I) wherein (A1q2) has the same meaning as in the final product and a substituted piperidine (intermediate II) in which R1, A and (Alk2) have the meanings intended for the final product. The bromoalkyl ester is commercially available or is readily prepared by known techniques. The alkylation reaction can be carried out using conventional techniques. Usually the bromoalkyl ester E and the intermediate II are mixed in a molar ratio of about 1: 2 in a solvent such as benzene and the reaction mixture is subjected to heating under reflux under an inert atmosphere for several hours. Alternatively the bromoalkyl ester E, the intermediate II and the triethylamine can be mixed in equimolar amounts. Intermediate III is recovered from the reaction mixture and purified by known techniques. For example, the reaction mixture is concentrated under reduced pressure, then it is partitioned between diethyl ether and filtered to give intermediate III, as shown. The next step of the reaction scheme is an amidation reaction between intermediate III and a substituted amine represented by the general formula 2. The substituted amine 2 is chosen so that R " and (Alk3) have the meanings:

which are intended for the final product of general formula IX. The substituted amine 2 is either commercially available or readily prepared by known techniques. The substituted amine 2 and intermediate III are reacted in a molar ratio of about 1: 1 to 2: 1 in the presence of 2-hydroxypyridine and heated to 60 ° C for several hours. The resulting product can be extracted and purified by known techniques. The solution is poured into water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The final product is then purified using known chromatographic techniques, such as flash chromatography.

Reaction Scheme X

Compounds of formula IX, prepared according to the methods described above, can be converted into the corresponding amidines by reaction with triethyloxonium tetrafluoroborate and then with an amine of the general formula R 1, -NH 2 to give a compound of formula X.

R '0 R " N-A- (Alk), -N (Alk), -B- (Alk)

Formula IX (1) Et30BF4 (2) Rw NH2

R 'm -NR " N-A- (Alk1) -N- (Alk2) -CN- (Alk3) -CH.

Formula X-30-

The general formula X corresponds to the general formula A in which A is -CHO or -CH-, D represents a group of R 2, (A1q2), (Alk2), R1, R2, R3 and R4 are as defined in formula but for the general formula A. The amine is selected from the group consisting of R 1, is as defined for R1 in the final product An amide prepared according to Reaction Scheme IX is dissolved in methylene chloride and treated with an approximately equimolar amount of triethyloxonium tetrafluoroborate, followed by an excess of the appropriate substituted amine The final product of formula X can be purified by known techniques.

Similarly, other complex compounds according to the present invention may be prepared by the following methods.

Reaction Scheme XI

Compounds of formula XI may be prepared by the procedure depicted in Reaction Scheme XI. The general formula XI corresponds to the general formula A in which A represents a -CH- or -CH 2 group; D represents a group of the formula R 1 and R 2 represents a group of (A1q2), (A1q3), R *, R ', R1 and R2 are as defined above for the general formula A.

II ι

Br - (AI q 2) -C 0 - Et + H N - (Al q 3) -CH 3 Alkylation

Alkylation

Et-O-O-C- (Alk2) -N- (A1q3)

- CH 3 +

- A- (A1q1) -NH. R "

Intermediate II

Amidation

R " 0 R 'π. r -A- (Alk1) -N-C- (Alk2) -N- (Alk3) CH3

Formula XI The first step of the reaction sequence is N-alkylating an appropriately substituted amine of Formula 2 with a bromoalkyl ester of Formula II. Suitable propionic compounds are a bromoalkyl ester of formula (I) in which (IA) has the desired meaning for the final product, and a substituted alkylamine of formula 2 wherein R * and (A1q3) have the meanings intended for the final product. Compounds 1 and 2 are marketed or can be readily prepared by known techniques. The alkylation reaction may be carried out by known techniques. Typically the bromoalkyl ester and the substituted amine 2 are mixed in a molecular ratio of about 1: 2 in a solvent such as benzene and the reaction mixture is heated under reflux under an inert atmosphere for several hours. Alternatively, the bromoalkyl ester 1, substituted alkylamine 2 and triethylamine may be mixed in equimolar amounts. The alkylamine ester 3 is then recovered,

upon application of the reaction mixture under diethyl ether and filter the general formula 3, as well as the reaction mixture and purified as known. For example, the reaction mixture is concentrated and then taken up to give the alkylamine ester shown. The next step of the reaction scheme is an amidation reaction between the alkylamine ester 2 and the intermediate II (of Reaction Scheme IVA) is chosen so that R 1, R 2, R 3, and (A1q2) have the meanings intended for the final product represented by the general formula XI. the alkylamine ilether intermediate 3 is reacted > in a molar ratio of about 1: 1 to 2: 1 in the presence of 2-hydroxypyridine and heated at 60 ° C for about 72 hours to give a compound of formula XI. The final product can then be extracted and purified according to known methods. The solution is poured into water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The final product is then purified by the application of known chromatographic techniques, such as flash chromatography. .

Reaction Scheme XII

An amide of formula XI, prepared according to the method described above, may be reacted with an amine of the general formula NR11 to obtain a compound of general formula XII.

0 R " R (1) Et30BF4 (2) rH2 • A- (Alk1) -CN- (Alk2) -N- (Alk3) -CH3

Formula XI

R "

R N-A- (Alk1) -CN- (Alk2) -N- (Alk3) -CH.

Formula XII The formula XII corresponds to the general formula A in which R * " -1¾ R "  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒD represents a group of formula - (CH2) n, alkylene having zero carbon atoms and (A1q2, (Alk2), R2, R2 and R3 have the meanings given for general formula A.

The amine is chosen so that R m has the meanings intended for the final product. Dis-

an amide prepared according to the procedure described in Reaction Scheme XI is dissolved in methylene chloride and treated with an approximately equimolar amount of triethyloxonium tetrafluoroborate followed by an excess of the appropriate substituted amine. The reaction mixture is usually stirred overnight at ambient temperature and then heated under reflux. The solution is then cooled to room temperature, diluted with aqueous sodium hydroxide, dried over a drying agent such as magnesium sulfate, and concentrated under reduced pressure. The obtained oil can be purified by conventional techniques. The oil can be dissolved in diethyl ether, filtered and treated with anhydrous hydrochloric acid. The resulting precipitate is filtered and recrystallized from ethyl acetate / alcohol, isopropyl alcohol to give the final product XII.

The compounds of the general formulas XIII and XIV may be prepared according to the following reaction schemes.

Reaction Scheme XIII

A mixed compound, amine and amide, of formula XIII, can be prepared by the method described below. The general formula XIII corresponds to the general formula A in which A represents a -

CHO R '

-CH-, D represents a group of the formula -N-, R 'and R' is a group of the formula -NC- and (Alk), (Alk%) ( A1q2) * R1 > R " > R 2 and R 3 are as defined above for the general formula A. 0, K Amidation HN - (AIq2) -OH + CIZ / A3) - CH3 * 1 2

HO R " 0 A1 q 2) - N - C - (A1 q 3) - CH, O-Tosylation

TsO-R " 0 (A1q2) -N-C- (Alk3) -CH3

N-A- (Alk,) -NH

Intermediate II N-Alkylation R '" (A1q) -Î ± - (Alk2) -N-C- (ALq3Ι Q

Formula XIII '2,

The first step of the reaction is the amidation of the acid chloride 2 with an amino alcohol. The acid chloride 2 and the amino alcohol J 1 are chosen so that R 2, (A1q 2) and (Al q 3) have the meanings intended for the final product. Compounds 1 and 2 are commercially available or readily prepared by well-known techniques. The reactants are mixed in approximately equimolar amounts in the presence of one equivalent of triethylamine in methylene chloride at a temperature comprised between 0 ° C and 10 ° C under an inert atmosphere. The resulting product is recovered from the reaction mixture and purified by standard techniques such as flash chromatography. The second step of the reaction scheme is 0-tosylation of alcohol 3 to provide a tosylate 4 by the application of conventional techniques. The third step of the reaction scheme is the N-alkylation of the tosylate 4 through Intermediate II of Reaction Scheme IV A. The intermediate II is chosen so that R 2, R 2 > A, (Alk%) and R 'have the meanings intended for the final product. The reactants are mixed in a molar ratio of about 1: 1 to 1: 2 in a solvent such as benzene, and the reaction mixture is heated under reflux under an inert atmosphere for about 16 hours. The resulting product can be purified by well known techniques. The obtained oil can be dissolved in diethyl ether, washed with an aqueous solution of sodium hydroxide,

filtered and treated with anhydrous hydrochloric acid. The resulting precipitate can be filtered and recrystallized from ethyl acetate / isopropyl alcohol, for example, to give the final product of formula XIII as the hydrochloride.

Reaction Scheme XIV

A compound of formula XIII, defined and prepared as described above, may be reacted with triethyloxonium tetrafluoroborate and an amine of the general formula ## STR4 ## to obtain a compound of formula XIV. (1) Et-OBF-α- (2) R 1 " NH2

N-A- (Alg1) -N- (Alk2) -CN, (Alk3) -CH3 Formula XIII% N-A- (Alk

f R " N R " ) -N- (Alk2) -CN- (Alk3) -CH

Formula XIV -38-

The general formula XIV corresponds to the general formula wherein A represents a group -CH2 - or -CH-, D represents a group of the general formula -N- and E represents a group of the general formula RUI N R " (Alk2), (Alk3), R1, R2, R3, R4 and R4 are as defined above. The amines of the formula ## STR4 ## are chosen so that R 1 has the meanings intended for the final product of formula XIV.

An amide prepared according to Reaction Scheme XIII is dissolved in methylene chloride and treated with an approximately equimolar amount of tri-ethyloxonium tetrafluoroborate followed by an excess amount of the appropriate substituted amine. The reaction mixture is stirred overnight at ambient temperature and then heated under reflux. The resulting product can be extracted and purified by the application of known techniques. The solution is then cooled to room temperature, diluted with sodium hydroxide, dried over a drying agent such as magnesium, and concentrated under reduced pressure. The resulting oil can be dissolved in diethyl ether, filtered and treated with anhydrous hydrochloric acid. The resulting precipitate can be filtered and recrystallized from ethyl acetate / isopropyl alcohol to give a final product of formula XIV.

Reaction Scheme XV

The compounds of formula XV may be prepared according to the following reaction scheme. The general formula XV corresponds to the general formula A in which A represents a group P 1 H -C-, D and E each represent a direct bond and (A1q 2), (A1q 0) and (A1q 3) are represented by (Alk), in L. where X is an integer from 1 to 18. CH 2 - (Alk) - CSN + MeOH HCl X - 2 - * Pinner reaction

NH

II

CH-; - (Alk) -C-OMe HCl X

R 3

Intermediate A

Amidation

The first step of the reaction sequence is the completion of a Pinner reaction between an alkyl cyanide] and an appropriate alcohol, such as methanol, the appropriate starting compound is an alkyl cyanide of formula in which Alqv has the meaning defined for the final product. The compounds of Formula I are readily available or commercially available from available compounds by the application of known techniques. Pinner's reaction may be effected by known techniques. Usually, approximately equimolar amounts of an alkyl cyanide with an appropriate alcohol 2 are contacted with a solvent such as diethyl ether. The reactants are mixed and cooled to about 0 ° C, followed by the introduction of an acid, for example hydrochloric acid to saturation. The reaction mixture is stirred overnight. The imidate ester hydrochloride obtained by the above reaction can be recovered from the reaction mixture and purified by the use of conventional techniques. For example, the resulting precipitate is concentrated under reduced pressure, triturated with diethyl ether, filtered and air dried to give the imidate ester 3 as the hydrochloride. The second step of the reaction scheme is to carry out an amidation reaction. The compound obtained above is mixed with an approximately equimolar amount of an intermediate A compound of Reaction Scheme A in methanol and left at room temperature overnight. The final product and can be separated purified by conventional techniques. For example, the reaction mixture is concentrated under reduced pressure, triturated with diethyl ether, the resulting solid product is collected by vacuum filtration, washed with diethyl ether and air dried, yielding the product end of general formula XV.

Reaction Scheme XVI

Compounds of formula XVI may be prepared according to the following method. The general formula XVI corresponds to the general formula I in which A is -CHX, in which X represents a hydrogen atom or a methyl group and D and E each represent a direct bond. R

Intermediate + X-CO- (Alk1) -D- (Alk2) -E- (Alk3) -CH3

THE

NaBH 4 CN NaOAc MeOH reductive amination

Intermediate A is prepared in the manner described in detail above in Reaction Scheme A. Intermediate A is chosen such that (a) R 2 and R 2 have the meanings intended for the final product. The aldehyde or ketone of Formula (I) is chosen so that X, (Alk), (Alk) and (A1q2) have the meanings defined for the final product. The compounds of Formula I are commercially available or are prepared readily from available compounds by the application of known techniques.

Intermediate A is treated with hydrochloric acid in methanol and the solvent is removed in vacuo. The resulting chlorohydrate is mixed with sodium acetate in a ratio of about 1: 2 together with 4 R molecular sieves and an approximately equimolar amount of the appropriate aldehyde or ketone of formula U 1 mg of green bromocresol in anhydrous methanol and the mixture is warmed to near the temperature of -40-

flow for about 1 hour and cooled, followed by the addition of sodium cyanoborohydride in a ratio of about 2: 1 with intermediate A. The resulting solution was refluxed until thin layer chromatography (TLC) shows that the reaction is complete. The desired product of general formula XVI can be extracted and purified according to known methods. For example, the solvent is removed in vacuo, the residue is diluted with 10% sodium hydroxide, the aqueous layer is extracted with diethyl ether and the extracts are dried over magnesium sulfate. The product may be purified by standard chromatographic methods.

Reaction Scheme XVII

Compounds of formula XVII may be prepared according to the following method. The general formula XVII represents compounds of formula A in which A represents a group -CH (CF 3) - and R 1, R 2, R 3, R 4, D, E, (Alk 2, (Alk 2) and (Alk 3) have the meanings defined above for the general formula A. [

(D-HCl) f (2) 10¾ Pd / C, H2

Wn C02CH2CH 3

(Alk1) -D- (Alk2) -E- (Alk3) -CH3 3 (1) δ4 (2) NaCNBH3

(Alk 1) -D- (Alk 2) -E- (Alk 3) -CH 3 LAH 4

The 3- or 4-substituted piperidinylidene propionate of formula (1) is prepared in the manner previously described in detail in Reaction Scheme A (compound 3, supra). The protecting group (PG) is removed and the olefin is first reduced by treatment of the substituted piperidine with an appropriate acid, such as a saturated solution of hydrochloric acid, and then the solvent is removed in vacuo. -4-

The resulting residue is dissolved in anhydrous ethanol and transferred to a hydrogenation vessel. A 10% palladium-on-charcoal is added over charcoal and hydrogen is introduced into the vessel at a pressure of about 50 psi (3.5 kg / cm @ 3). After stirring for several hours, the catalyst is filtered through Celite, for example, and the solvent is removed in vacuo to give 3- or 4-substituted piperidinyl propionate hydrochloride of Formula 2. Thereafter, the 3- or 4-substituted piperidinyl propionate hydrochloride of formula 2 is reacted with trifluoromethyl ketone as represented by 3. Trifluoromethyl ketone 3 is prepared as described in Reaction Scheme XVII A below.

Reaction Scheme XVII A A1 CF,

OH + EtMgBr CF 3, OMBBr

Mg A2. CH3- (Alk3) -E- (Alk2) -D- (Alk1) -BrO2 and CF3 N OMgBr3 * A3. CH3- (Alk3) -E- (Alk2) -D- (Alk1) -MgBr 4 * O-CF3 X1, (Alk1) -D- (Alk2) -E- (Alk3) -CH3 1 (Reaction Scheme XVII) -4-

In Reaction Scheme XVII A, (Alk), (Alk), (Alk3), D and E have the meanings as defined above for the general formula A, provided that D or E do not represent groups of the formula R " R1 " -N R " R " or R " -NR "

II | II I I > " -CN-N-C-N, -N-C or -N-C-

First, magnesium trifluoroacetate bromide is prepared according to Reaction Scheme XVII A1. To a solution of trifluoroacetic acid V, dissolved in a suitable organic solvent, such as anhydrous diethyl ether, is added an approximately equimolar amount of a Grignard reagent, such as ethyl magnesium bromide (EtMgBr), in solution in anhydrous diethyl ether at low temperature (-5 ° C) under a nitrogen atmosphere. The reaction mixture is then allowed to resume at room temperature.

The desired alkyl magnesium bromide is then prepared according to Reaction Scheme XVII A2. The appropriate alkyl bromide 3] is selected such that (Alk), (Alk2), (Alk3), D and E have the meanings defined for the final product of formula 4. The 3 'alkyl bromide is either a known product or can be prepared by generally known methods. The alkyl bromide in solution in anhydrous diethyl ether is added magnesium in anhydrous diethyl ether (equimolar amounts of 3% alkyl bromide and magnesium). The reaction mixture is stirred at room temperature until the magnesium is dissolved.

To the vessel containing 2% magnesium trifluoroacetate bromide is added 4-alkyl magnesium bromide in approximately equimolar amounts at a low temperature (-5 ° C) under an atmosphere of nitrogen. The reaction mixture is stirred for about 1 hour at ambient temperature, refluxed for several hours, cooled to about 0 ° C, and then hydrolyzed by the dropwise addition of 5N hydrochloric acid, for example. Then the phases are separated, the aqueous phase is extracted with ethyl acetate, the organic extracts are combined and washed with a saturated aqueous solution of cooled sodium hydrogen carbonate and dried. Evaporation gives an oil which can be purified by distillation to provide the trifluoromethylalkyl ketone 3 according to Reaction Scheme XVII A.

The trifluoromethylalkyl-C 3 -tone and the substituted piperidine Z are then mixed in approximately equimolar amounts in the presence of an excess of triethylamine and anhydrous methylene chloride at a temperature of about 10 ° C under atmospheric of nitrogen. Titanium tetrachloride is added dropwise over about 10 minutes in a molar amount approximately half the molar amount of trifluoromethylalkyl ketone. The reaction mixture is stirred at ambient temperature for approximately 48 hours, then diluted carefully with a methanolic solution of an excess of sodium cyanoborohydride. The reaction mixture is acidified with 5N hydrochloric acid and then basified with 5N sodium hydroxide, for example. The desired product is extracted with ethyl acetate, dried over magnesium sulfate and evaporated, yielding a substituted trifluoromethylalkyl-piperidine ester of Formula 4.

Finally, the substituted trifluoromethylalkyl-1-piperidine ester 4 is reduced with the formation of the corresponding alcohol of formula 5. To an ice-cooled solution of the substituted trifluoromethylalkyl-piperidine ester in dry tetrahydrofuran is added an excess of diisopropyl aluminum hydride in toluene. The resulting mixture is stirred for about 1 hour and carefully diluted with methanol at 0Â ° C. The solution is then diluted with diethyl ether and washed with 10% sodium hydroxide. The resulting emulsion is filtered through Celite, the organic phase is separated, dried over magnesium sulfate and the solvent is removed in vacuo to give the product of general formula 5.

Examples of compounds of the present invention are the following: 1. 4- (2-hydroxy-1-methylethyl) -N- (3-methylbutyl) -1-piperidinobuhamamide. 2. p-methyl-1- (4- (3-methylbutyl) amino] butyl] -4-piperidineethanol. 3. 1- (1-amino-4-methylpentyl) -β-methyl-4-piperidineethanol. 4. N-Butyl-4- (2-hydroxy-1-methylethyl) -N-methyl-1-piperidinebutanamide. 5. 4- (2-hydroxy-1-methylethyl) -1-piperidinebutanenitrile. 6. 1 - (4-aminobutyl) -β-methyl-4-piperidineethanol. 7. N- [4- [4- (2-hydroxy-1-methylethyl) -1-piperidinyl] butyl] -4-methylpentanimidamide. 8. 1- (1-iminooctyl) -β-methyl-4-piperidineethanol. 9. 1 - (1,5,9-trimethyldecyl) -j-methyl-4-piperidineethanol. 10. 2- [1- (trifluoromethyl) undecyl-4-piperidinyl] -propanol. The following assays are used to evaluate the compounds with respect to their ability to inhibit 2,3-cyskene-1-anosylcyclase or epoxidase. Microsoils, prepared by ultracentrifugation of rat liver homogenates, are incubated at 37øC for 45 minutes in the presence of 60æM3 H-squalene, 2.0 mM NADPH, 0.01 mM FAD and the fraction of supernatant from the microparticles preparation. Blank, in which NADPH was omitted, were run concurrently with the test compounds. The compounds are assayed at concentrations of from 0.0 to 100.0 ÂμM. Method 1

After incubation, the samples are saponified, standards are attached to each sample, and then the reaction products are extracted with hexane. The hexane extracts are dried, then redissolved in chloroform. The reaction products contained in the extracts are then separated by thin layer chromatography. Strips containing the reaction products are removed from the thin layer chromatography plates and their radioactivity determined by means of a scintillation counter. Finally the IC is calculated. Method 2

After incubation reactions are stopped by addition of a chloroform / methanol mixture, standards are added, then the reaction products and standards are extracted with chloroform. Dry the chloroform extracts and dissolve the residue in toluene / methanol. The reaction products and the standards contained in the dissolved residue are separated by high performance liquid chromatography (HPLC). The radioactivity of the chromatographic peaks containing the reaction products is determined by means of a scintillation counter connected in series to the HPLC column. The Clâ "¢ is calculated based on the radioactivity of the con-50 and the samples. -51-

-esqualene-lanosterol cyclase

The compounds of the present invention are usable both in the free base form and in the form of acid addition salts. However, acid addition salts are a more convenient way to use and, in practice, the amounts of salt corresponding to the use of free base are used. The expression " pharmaceutically acceptable acid addition salts " applies to any non-toxic organic or inorganic acid addition salt of the bases of the compounds of the present invention referred to above. Representative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids and methacrylic acid salts, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Representative organic acids which form suitable salts include sulfonic acids, such as p-toluenesulfonic acid, methanesulfonic acid and 2-hydroxyethanesulfonic acid. The salts of the mono- and di-acid salts can be formed and these salts can exist either in a hydrated form or in a substantially anhydrous form. The acid salts are prepared by the application of conventional techniques, such as dissolving the free base in an aqueous or aqueous-alcoholic solution or in another suitable solvent containing the appropriate acid and isolated by evaporation of the solution, or by reaction of the free base in an organic solvent, in which case the salt is separated directly or can be obtained by concentration of the solution. The preferred route of administration is the oral route. For oral administration the compounds may be prepared in the form of solid or liquid compositions, such as capsules, tablets, troches, lozenges, candies, powders, solutions, suspensions or emulsions. Solid unit dosage forms may be capsules, which may be hard gelatin or soft gelatin containing, for example, surfactants, lubricating agents and inert fillers, such as lactose, sucrose, calcium phosphate and corn starch. In a further variant the compounds of the present invention may be compressed with conventional compression bases, such as lactose, sucrose and corn starch, in association with binding agents such as acacia, corn starch or gelatin, disintegrating agents for promoting fragmentation and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch and guar gum; lubricating agents intended to improve the flow of the granulations for compression and to prevent adhesion of the compression material to the surfaces of the die cores and punches of the tablets, for example talc, stearic acid or stearate: magnesium, calcium or zinc, coloring agents and flavoring agents to improve the aesthetic qualities of the tablets and to make them more acceptable to patients. Exemplary suitable for use in the liquid forms include -53-

diluents such as water and alcohols, for example ethanol, benzyl alcohol, and polyethylene alcohols, with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsifying agents.

The compounds of the present invention may also be administered parenterally, i.e. subcutaneously, intravenously, intramuscularly or interperitoneally, in the form of injectable doses of the compounds in a physiologically acceptable solvent with a pharmaceutical carrier , which may be a sterile liquid or a mixture of liquids, such as water, sodium chloride solution, aqueous dextrose solution and related sugar solutions, an alcohol, such as ethanol, iso-propanol or hexadecyl alcohol, glycols , such as pro-pylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, esters such as poly (ethylene glycol) 400 , oils, fatty acids, esters of fatty acids or glycerides or glycerides of acetylated fatty acids, with the possible addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, such as, for example, pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents or other pharmaceutically acceptable adjuvants. Examples of oils which may be used in the parenteral compositions of the present invention are petroleum-derived oils, animal, vegetable and parent oils,

for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petro-latum and mineral oil. Suitable fatty acids include oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal, ammonium and triethylamine fatty salts and suitable detergents, such as cationic detergents, for example, dimethyldialkylammonium halides, alkylpyridinium halides and alkylamines acetates; anionic detergents, for example, alkylsulfonates, arylsulfonates and olefin sulfonates, alkyl and olefinic esters and sulfates and sulfosuccinates and mono-glycerides; nonionic detergents for example, fatty amine oxides, fatty acid alkanolamides and polyoxyethylene-polypropylene copolymers; and amphoteric detergents, for example, alkyl betaines-aminopropionates and quaternary ammonium 2-alkylimidazoline salts, as well as mixtures.

The parenteral compositions of the present invention usually contain about 0.5 to about 25% by weight of active component in solution. Preservatives and buffering agents may also be advantageously used. In order to minimize or eliminate irritation at the injection site, these compositions may contain a nonionic surfactant having a hydrophyl lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant in these compositions ranges from about 5 to about 15% by weight. The surfactant may have a single component with the above-mentioned hydrophile-lipophilic balance or may be a mixture of two or more components with the appropriate hydrophilic-lipophilic balance. Examples of surfactants used in the parenteral compositions are those of the class of polyethylene sorbitan fatty acid esters, for example sorbitan monooleate and high molecular weight addition products of ethylene oxide with a hydrophobic base , formed by condensation of propylene oxide with propylene glycol. The precise amount of compound or compounds to be used, i.e., the amount of compound or compounds sufficient to provide the desired effect, depends upon various factors, such as the compound used, the type of administration, the stature, the age and the species of the animal ; the route, time and frequency of administration and the intended physiological effect. In particular cases, the amount administered may be determined by the application of conventional interval determination techniques.

The compounds are preferably administered in the form of a composition containing the compound in admixture with a pharmaceutically acceptable carrier, i.e. a carrier which is chemically inert to the active compound and which has no effect harmful or toxic under the conditions of use. These compositions may contain about 0.1 Âμg or -56-

less than 500 mg of active component per ml of carrier to about 99% by weight of the active compound in association with a pharmaceutically acceptable carrier.

The compounds may also be incorporated into any inert carrier so that they can be used in routine serum tests, blood, urine levels, etc., in accordance with standard techniques.

The compositions may be in solid forms, such as tablets, capsules, granules, feed mixtures, food supplements and concentrates, powders, granules, etc .; as well as in liquid forms, such as sterile injectable suspensions, suspensions or solutions for oral administration. Pharmaceutically acceptable carriers may include excipients, for example, dispersing surfactants, suspending agents, blowing agents, lubricating agents, flavoring agents and coloring agents. Suitable excipients are described, for example, in texts such as Remington's Pharmaceutical Manufacturing, Easton, Pennsylvania, Mack Publishing Co., 13th ed., 1965.

The following examples are set forth to illustrate the present invention but are not to be construed as limiting this in any sense. -57- /

Example 1a

Preparation of 2- [1 (phenylmethyl) -4-piperidinylidene] propanoic acid ethyl ester To a stirred solution of triethyl 2-phosphonopropionate (5.72 g, 24 mmol) in dry tetrahydrofuran (250 mL) at -78 ° C and under argon, a solution of 16.3 ml (26 mmol) of n-butyllithium in hexane was added. The resulting anion was stirred for an additional 10 minutes and 3.79 g (20 mmol) of N-benzyl-4-piperidinone in 50 ml of tetrahydrofuran was added dropwise through a syringe.

The mixture was then stirred for 10 minutes, warmed to room temperature and stirred for an additional 17 hours. The solution was then washed with saturated ammonium chloride solution (100 ml), washed twice with 10% sodium hydroxide, dried over magnesium sulfate and evaporated to give 6.58 g of an unpurified oil which was purified by chromatography using 25% ethyl acetate / hexane as eluent. Removal of the solvent in vacuo was added 5.25 g (96% yield) of a colorless oil which was identified as 2- [1- (phenylmethyl) -4-piperidinylidene] propanoic acid ethyl ester from the The following spectral data were obtained: MS, CI / CHâ,,; m / z 274 (M + H) (base), 228 (M + H-EtOH), 196 (M + H-C6 H9). -58-

Example 1b

Preparation of 1-C1- (phenylmethyl) -4-piperidinylidene-1-propanol. To an ice-cooled stirred solution of 1-C1- (phenylmethyl) -4-piperidinylidene] propanoic acid ethyl ester (550 mg, 2.0 mmol) in dry tetrahydrofuran (50 ml) , 0 ml (6.0 mmol, 1.5 M) of diisopropyl aluminum hydride in toluene. The resulting mixture was stirred for an additional hour and carefully diluted with methanol at 0 DEG C. The solution was then diluted with diethyl ether and washed with 10% sodium hydroxide . The resulting emulsion was filtered through Celite, the organic phase was separated, dried over magnesium sulfate, and the solvent was removed by rotary evaporation to give 460 mg of an oil which was identified as 1-C - (phenylmethyl) -4-piperidinylidene] propanol was obtained based on the following spectral data: HRMS calcd for C 15 H 21 NO: 232, 1701; Determined; 232, 1699.

Example 2

Preparation of 1- (1,5,9-trimethylenedioxy) -β-methyl-4-piperidineethanol

A 300 mg (12.2 mmoles) sample of 1-chloro-1- (phenylmethyl) -4-piperidinylidene-ethyl ester was treated with a saturated solution of hydrochloric acid in methanol (HCl / CH 3 OH) and the solvent was removed by rotary evaporation. The resulting residue was dissolved in 25 ml of abs. Ethanol and transferred to a Parr hydrogenation vessel. A catalytic amount (101 mg) of 10% palladium on charcoal was added and hydrogen was introduced into the vessel under pressure

O of 3.5 kg / cnr (50 psi). After stirring for 37 hours, the catalyst was filtered through Celite and the solvent was removed in vacuo. The resulting residue was again treated with the hydrochloric acid / methanol mixture and discarded in vacuo. The resulting hydrochloride was blended with 180 mg (2.2 mmol) of sodium acetate, 2.0 g of 4A molecular sieves and 300 mg (1.5 mmol) of 6,10-dimethyl-2-undecanone and 1 mg bromocresol green in 20 ml anhydrous methanol. The mixture was heated at reflux temperature for 1 hour, cooled and 138 mg (2.2 mmol) of sodium cyanoborohydride added. The resulting solution was refluxed for 30 hours, at which time thin layer chromatography showed the reaction to be complete. The solvent was removed in vacuo and the residue was diluted with 20 mL of 10% sodium hydroxide. The aqueous layer was extracted with three portions of 30 ml of diethyl ether and the retinoic extracts were dried over magnesium sulfate. Removal of the solvent in vacuo gave an oil which was dissolved in 20 ml of anhydrous tetrahydrofuran and treated with an excess of lithium aluminum hydride (10 ml, 1.0M solution in diethyl ether). After 30 minutes, the reaction was stopped according to method -60

de Fieser & Fieser, supra, and the solvent was removed to give an oil which was purified by silica gel chromatography using first a 25% ethyl acetate / hexane solution and then a 20% methanol / chloroform as eluent. Concentration of the methanol / chloroform fractions gave 247 mg (69% yield) of an oil which was identified as 1- (1,5,9-trimethyl-1) -β-methyl-4-piperidine-ethanol based on the data following spectral data: MS, EI / 70EV; m / z 325 (M +), 310 (MH +), 170 (base).

Example 3

Preparation of 4-methyl-4-piperidineethanol To a solution of 1.5 g (5.5 mmol) of 2 - [(phenylmethyl) -4-piperidinylidene] propanoic acid ethyl ester in 50 ml of acetic acid introduced into a Parr hydrogenation vessel was added 500 mg of 10% palladium on charcoal. Hydrogen was charged to the pressure of 3.5 kg / cm (50 psi). After stirring for 18 hours, the solution was filtered through Celite and the solvent was removed in vacuo. The resulting acetate was dissolved in 50 ml of dichloromethane in a 250 ml round bottom flask. To this solution was added 1.33 g (6.1 mmol) of di-5-butyldicarbonate and 5 ml of triethylamine. After stirring for 30 minutes at ambient temperature, the solvent was removed and the residue dissolved in 100 ml of diethyl ether. The ether layer was washed with 2N hydrochloric acid and dried over magnesium sulfate, the solvent removed,

J

The residue was chromatographed on silica gel eluting with a mixture of 10% ethyl acetate / hexane as eluent to give 1.57 g of carbamate. This product was dissolved immediately in 50 ml of tetrahydrofuran and treated with 12.0 ml (12.0 mmol) of diethylbutyl aluminum hydride at 0Â ° C under a nitrogen atmosphere. The solution was warmed to room temperature and allowed to stir for 15 hours. The mixture was cooled to 5 ° C and diluted by the careful addition of methanol. The resulting emulsion was diluted with 100 mL of diethyl ether and It was transformed through Celite. The solvent was removed, yielding 960 mg of protected alcohol (MS, CI / CH3 + M + H + + 244).

The alcohol obtained above was cooled to 5 ° C and dissolved in 25 ml of trifluoroacetic acid. After complete release of carbon dioxide the solvent was removed, the residue dissolved in 100 ml of diethyl ether and washed with 10% sodium hydroxide. Continuous extraction with diethyl ether from the basic layer gave 247 mg of β-methyl-4-piperidinoethanol which was identified based on the following spectral data: MS, CI / CH 4 m / z Γ M + H J + 144 ( base).

Example 4

Preparation of 4- (2-hydroxy-1-methylethyl) -N- (3-methylbutyl) -1-piperidinebutanamide hydrochloride To a stirred solution containing ethyl 4-bromobutyrate (995 mg, 5.1 mmole) 730 mg (5.1 mmol) of Î ± -methyl-4-piperidine-ethanol in 50 ml of absolute benzene was added 840 æl (5.1 mmol) of triethylamine. The mixture was refluxed under nitrogen atmosphere overnight. The solution was concentrated under reduced pressure, diethyl ether added and filtered. The filtrate was washed with 10% sodium hydroxide solution, the organic phase was collected, dried over magnesium sulfate and evaporated to give 4- (2-hydroxy-1 methylethyl) -1-piperidinebutanoic acid as product.

Thereafter, 1.0 g (3.9 mmol) of 4- (2-hydroxy-1-methylethyl) -1-piperidinebutanoic acid ethyl ester were combined with isopentylamine (850 mg, 9.8 mmol) and 367 mg (3.86 mmol) of 2-hydroxypyridine and heated together at 60 ° C in a sealed tube. After the whole reaction was considered (gas chromatography), the solution was poured into water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure to afford product to 4- (2-hydroxy-1-methylethyl) -N-3-methylbutyl) -1-piperidinebutanamide. This product was dissolved in diethyl ether and treated with anhydrous hydrochloric acid to give, after removal of the product, a solid which was purified by recrystallization to give 4- (2-hydroxy-1- methoxyethyl) -N- (3-methylbutyl) -1-piperidinobutanamide as the product.

Example 5

To a stirred solution of 4- (2-hydroxy-1-methylethyl) -piperidine-4-carboxylic acid, N- (3-methylbutyl) -1-piperidinebutanamide (prepared from 1.0 g (3.3 mmol) or hydrochloride by extraction of the base) was dissolved in 100 ml of anhydrous tetrahydrofuran at 0Â ° Under nitrogen atmosphere, a solution of 4.0 ml of lithium aluminum hydride (1.0 M) in diethyl ether was added dropwise via syringe. The resulting mixture was stirred at room temperature overnight and then heated under reflux. The solution was cooled, and the reaction was quenched by the addition of water and a 15% sodium hydroxide solution. The precipitate was filtered and the solvent was evaporated to give the product. This product was dissolved in diethyl ether and treated with anhydrous hydrochloric acid to give, after removal of the solvent, a solid which was purified by recrystallization gave 4-methyl-1- [4 - [(3-methylbutyl) amino] butyl] -4-piperidineethanol hydrochloride as the product. -64-

Example 6

Preparation of 1- (1-imino-4-methylpentyl) -methyl-4-piperidineethanol hydrochloride

First, 10.0 g (0.103 mol) of 4-methylvaleronitrile and 3.5 g (0.11 mol) of methanol were dissolved in 100 ml of diethyl ether, cooled to 0øC, saturated with anhydrous hydrochloric acid, and left to stir overnight. The resulting solution was concentrated under reduced pressure and triturated with diethyl ether. A precipitate formed which was filtered and air dried to give 4-methyl-pentanimidic acid methyl ester hydrochloride as the product. A solution containing a mixture of 1.0 g (7.0 mmol) of β-methyl-4-piperidine-ethanol and 1.16 g (7.0 mmol) of the hydrochloride of the product is stirred overnight at room temperature. The resulting precipitate was filtered to give 1- (1-imino-4-methylpentyl) -piperidine-1-carboxylic acid methyl ester ) -β-methyl-4-piperidineethanol,

V

Example 7

Preparation of N-butyl-4- (2-hydroxy-1-methylethyl) -N-methyl-1-piperidinebutanamide hydrochloride

1.0 g (3.9 mmol) of 4- (2-hydroxy-1-methylethyl) -1-piperidinebutanoic acid ethyl ester are treated with N-methylbutylamine (854 mg, 9.8 mmol) and 367 mg ( 3.86 mmol) of 2-hydroxypyridine which were heated together at 60 ° C in a sealed tube. After considering the complete reaction (by gas chromatography), the solution was poured into water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure to give the product . This product was dissolved in diethyl ether and treated with anhydrous hydrochloric acid to remove the solvent to give a solid which was purified by recrystallization to give N-butyl-4- (2-hydroxy- 1-methylethyl) -N-1-piperidinebutanamide as the product.

Example 8

Preparation of N- [4-C- (2-hydroxy-1-methylethyl) -1-piperidinyl] butyl] -4-methylpentanimidamide hydrochloride To a stirred solution containing 1.04 g (7.0 mmol) of 4- -bromobutyronitrile and 1.0 g (7.0 mmol) of 4-methyl-4-piperidine-ethanol in 50 ml of anhydrous benzene was added 1.15 ml of 66% (8.4 mmol) of triethylamine. The mixture was refluxed under nitrogen atmosphere overnight. The solution was concentrated under reduced pressure, diethyl ether was added and the filtrate was filtered. The filtrate was washed with 10% sodium hydroxide, the organic phase was collected, dried over magnesium sulfate, (2-hydroxy-1-methylethyl) -1-piperidinebutanenitrile as the product. To a stirred, ice-cooled solution of 4- (2-hydroxy-1-methylethyl) -1-piperidinebutanonitrile (1.0 g, 4.8 mmol) in dry tetrahydrofuran (50 ml) To a nitrogen atmosphere, 5.0 ml (1.0 M) of lithium aluminum hydride in diethyl ether was added dropwise via syringe. The resulting mixture was stirred at room temperature overnight and then heated under reflux. The solution was then cooled and quenched by the addition of water and a 15% sodium hydroxide solution. The precipitate was filtered and the solvent was evaporated to give 1- (4-amino-butyl) -β-methyl-4-piperidine-ethanol as the product.

A solution containing a mixture of 1.0 g (4.7 mmol) of 1- (4-aminobutyl) -4-methyl-4-piperidineethanol and 1,16 (7.0 mmol) of 4-methyl-pentanimidic acid methyl ester hydrochloride in anhydrous methanol, the solvent was concentrated and diethyl ether added. The resulting precipitate was filtered to give, as a white powder. W-f 4-7 4- (2-hydroxy-1-methylethyl) -1-piperidinyl 7-butyl-4-methylpentanimidamide hydrochloride.

Example 9-methyl-

Preparation of 1- (1-imino-octyl) -piperidine-ethanol hydrochloride

10.0 g (0.079 mole) of octyl cyanide and 2.56 g (0.08 mole) of methanol were dissolved in 50 ml of diethyl ether, cooled to 0Â ° C, treated with anhydrous hydrochloric acid and stirred overnight. The resulting solution was concentrated under reduced pressure and triturated with diethyl ether. A precipitate formed which was filtered and air dried to give, as the product, octanimidic acid methyl ester hydrochloride.

A solution containing a mixture of 1.0 g (7.0 mmol) of 4-methyl-4-piperidine-ethanol and 1.36 g (7.0 mmol) of octanedicarboxylic acid methyl ester hydrochloride in anhydrous methanol, the solvent was concentrated and diethyl ether added. The resulting precipitate was filtered and dried to give 1- (1-iminooctyl) - N -methyl-4-piperidineethanol hydrochloride as the product. -68-

Example 10

Preparation of 2 - [[1- (1-trifluoromethyl) -undecyl-4-piperidinyl] -propanol.

Preparation of magnesium trifluoroacetate bromide (1) To a dry flask containing 15 g (0.132 mmol) of trifluoroacetic acid and 50 ml of anhydrous ether was added a solution of ethyl magnesium bromide (66 ml of a 2 M solution in tetrahydrofuran, 0.132 mmol) in 50 mL of anhydrous diethyl ether at -5 ° C under nitrogen. The reaction mixture was allowed to resume at room temperature.

Preparation of Decanyl Magnesium Bromide (2) To a dry flask containing 2.64 g (0.11 mmol) of magnesium and 50 ml of anhydrous diethyl ether was added a solution of 24.3 g (0.11 mmol) of 1-bromodecane in 50 ml of anhydrous diethyl ether under nitrogen atmosphere. The reaction mixture was stirred at room temperature until the magnesium had dissolved.

Preparation of trifluoromethyl-2-dodecanone (3)

To the vessel containing the magnesium trifluoroacetate bromide (1) was added the solution of decane-magnesium bromide (2) at -5 ° C under a nitrogen atmosphere. -69-

The reaction mixture was stirred for 1 hour at ambient temperature, refluxed for 12 hours, cooled to 0 ° C and hydrolyzed by the dropwise addition of 50 ml of 5N hydrochloric acid. The phases were separated, the aqueous phase extracted with 2 × 20 ml ethyl acetate, the combined organic phases were combined with cooled sodium hydrogencarbonate solution, then with concentrated sodium chloride solution and dried over magnesium sulfate. Evaporation gave 14.1 g of a yellow oil which was purified by distillation yielding 10.1 g (38% yield) of trifluoromethyl-2-dodecanone as a clear oil, bp: 125Â ° C 0.1 mm Hg. 1 H-NMR (300 MHz, CDCl 3) <0.85 (3H, t), 1.30 (14H, br s), 1.65 (2H, m), 2.70 (2H, t); ¹H-NMR (CDCl)) δ -80.02 (s); MS (CI / CH 4) 239 (M + H), 169 (M + H-HCF 3).

Preparation of ethyl 2- (4-piperidinyl) propionate hydrochloride (4)

A 300 mg (12.2 mmol) sample of 2-C1- (phenylmethyl) -4-piperidinylidene] propanoic acid ethyl ester was treated with a saturated solution of hydrochloric acid in methanol and the solvent by rotary evaporation. The resulting residue was dissolved in 25 ml of absolute ethanol and transferred to a Parr hydrogenation flask. A catalytic amount (101 mg) of 10% palladium on charcoal was added and 2 was introduced into the hydrogen vessel at a pressure of 3.5 kg / cm (50 psi). After -70- / 4

stirred for 37 hours, the catalyst removed by filtration through Celite and the solvent was removed in vacuo. The resulting residue was again treated with hydrochloric acid in methanol and the solvent was removed in vacuo to give ethyl 2- (4-piperidinyl) propionate hydrochloride (4).

Preparation of 2- (1-trifluoromethyl) undecyl] -4-piperidinyl] propanoic acid ethyl ester (5) To a dry flask containing 4.0 g (16.8 mmol) of trifluoromethyl-2-dodecanone (3), 3.17 g (15.1 mmol) of ethyl 2- (4-piperidinyl) propionate hydrochloride, 5 g (50.4 mmol) of triethylamine and 80 ml of anhydrous methylene chloride, (8.4 ml of a 1 M solution in methylene chloride, 8.4 mmol) was added dropwise under nitrogen to the reaction mixture for 10 minutes. The reaction mixture was stirred at room temperature for 48 hours, carefully diluted with methanolic sodium cyanoborohydride (3.4 g, 50.4 mmol in 20 mL methanol). The reaction mixture was stirred for 1 hour, carefully washed with pH 5 with 5N hydrochloric acid, stirred for 30 minutes and then adjusted to pH 13 with 5N sodium hydroxide solution. The pre-extracted product was extracted with ethyl acetate (3 x 75 ml), dried over magnesium sulfate and evaporated to give 2- (1-trifluoromethyl) -undecyl- -4-piperidinyl] propanoic acid (5). -71-

Preparation of 2- [1- (1-Trifluoromethyl) -undec-4-piperidinyl] -propanol (6) To a stirred ice-cooled solution of 779 mg (2.0 mmol) of 1- [ 1- (1-trifluoromethyl) undec-4-piperidinyl] propanoic acid in 50 ml of anhydrous tetrahydrofuran was added 4.0 ml (5.0 mmol, 1.5 M) of diisopropylaluminum hydride in toluene. The resulting mixture was stirred for another hour and carefully diluted with methanol at 0 ° C. The solution was then diluted with diethyl ether and washed with 10% sodium hydroxide. The resulting emulsion was filtered through Celite, the organic phase was separated, dried over magnesium sulfate, and the solvent removed on a rotary evaporator to afford 2- [1- (1-trifluoromethyl) undec-4- piperidinyl) -7-propanol (6).

Claims (14)

-72- A process for the preparation of compounds of general formula in which Y represents -A- (Alk) -D- (Alk 2) -E- (Alk 2) -CH 2 in which A represents CH, CF. -CH2- or -CH- or a group of the general formula -C- in which R 'represents a hydrogen atom or a lower alkyl group, . D and E represent, each independently, a direct bond, a -C1-4 group or a group of the formula: 'R &quot; * -NR &quot;  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒMH-N, -N-, -CN, -CN, -N- · 11 -N-C where R &quot; and R &quot; ' are each independently a hydrogen atom or a C2-4 lower alkyl group with the proviso that E is not a hydrogen atom. -O-, or when D represents those groups, and E is not R? R &quot; '- N R &quot; A compound of the formula wherein R 1, R 2, R 3, R 4, N-C- or -N-C- when D represents those groups; and D and / or E do not represent a group of the formula R &quot; E, TLN R &quot; R &quot; 0 R &quot; N-Rm II 1 II 1 | C 1 -C 4 -alkyl or -C (O-C 1 -C 4) -alkyl when A is -CH 2 CH 2); (Alk2), (Alk2) and (Alk2) each independently represent a straight chain alkylenic group having zero to 5 carbon atoms and optionally 1 to 3 methyl groups as substituent (s) The condition of (A) 1) not having zero carbon atoms; or (Alk), (A 1) 2) and (A 2) are each independently a straight chain alkenylenic group having 2 to 6 carbon atoms and 1 to 2 double bonds and optionally 1 to 3 (s), as the substituent (s), represents a 3- or 4-membered piperidine ring having the general formula 2. A process according to claim 1 for the preparation of compounds of formula A in which R 2 represents a group of -76- formula characterized in that correspondingly substituted starting compounds are used. 3. A process as claimed in claim 1 for the preparation of 4- (2-hydroxy-1-methylethyl) N- (3-methylbutyl) -1-piperidinebutanamide and the the pharmaceutical point of view, characterized in that correspondingly substituted starting compounds are used. Wherein R 2 represents an alkyl group R 2 and R 3 each independently represents a hydrogen atom or a C 1-6 lower alkyl group is zero or an integer 1 to 3, and R 2 represents a hydrogen atom or a hydroxy or lower alkyl group and the pharmaceutically acceptable salts thereof, characterized in that a compound of the general formula 0-75- (CH 3 CH 2) 2 PCH (CH 2) n CO 2 CH 2 CH 3 in which Κ 3 and n are as defined above, with a compound of general formula in which R 2 is as defined above, and PG represents a protecting group, to give a compound of formula Wherein R2, R3 and PG are as defined above, and the resulting compound of formula 3 is reduced to give the desired compound. 4. A process according to claim 1 for the preparation of p-methyl-1- [4- (3-methylbutyl) amino] butyl] -4-piperidinoethanol, and its acceptable salts under Accordingly, the present invention relates to a pharmaceutically acceptable carrier. 5. A process according to claim 1 for the preparation of 1- (1-imino-4-methylpentyl) -methyl-4-piperidineethanol and the pharmaceutically acceptable salts thereof, characterized in that use of correspondingly substituted starting compounds. "77- 6. A process as claimed in claim 1 for the preparation of N-butyl-4- (2-hydroxy-1-methylethyl) -N-methyl-1-piperidinebutyrate, and the Accordingly, the present invention relates to a pharmaceutically acceptable carrier. 7. A process according to claim 1 for the preparation of 4- (2-hydroxy-1-methylethyl) -1-piperidinebutanenitrile and the pharmaceutically acceptable salts thereof. correspondingly substituted starting compounds. 8. A process according to claim 1 for the preparation of 1- (4-aminobutyl) -4-methyl-4-piperidineethanol and the pharmaceutically acceptable salts thereof. correspondingly substituted starting compounds. 9. A process according to claim 1 for the preparation of N- [4- [4- (2-hydroxy-1-methylethyl) -1-piperidinyl] butyl] -4-methyl-pentanimidamide, and salts thereof pharmaceutically acceptable salts, characterized in that correspondingly substituted starting compounds are used. 10. A process according to claim 1 for the preparation of 1- (1-iminooctyl) -β-methyl-4-piperidineethanol, * and pharmaceutically acceptable salts thereof, characterized in that correspondingly substituted starting compounds are used. 11. A process according to claim 1 for the preparation of 1- (1,5,9-trimethyl-decyl) -methyl-4-piperidineenoterol and the pharmaceutically acceptable salts thereof, characterized in that use of correspondingly substituted starting compounds. 12. A process as claimed in claim 1 for the preparation of 2- [1- (1-trifluoromethyl) undecyl] -4-piperidinyl] propanol and pharmaceutically acceptable salts thereof, characterized in that use of correspondingly substituted starting compounds. 13. A process according to claim 1 for the preparation of 2- (1-phenylmethyl) -4-piperidinylidene] -1-propanol, and pharmaceutically acceptable salts thereof, characterized in that correspondingly substituted starting compounds are used. 14. A process for the preparation of pharmaceutical compositions suitable for reducing the serum cholesterol level and treating fungal infections in mammals, characterized in that a therapeutically effective amount of a compound of formula A prepared by the process according to claim 1 with inhibitory action of cholesterol synthesis in mammals and fungi with an inert carrier acceptable in pharmacy, Lisbon, July 23, 1991